Systems and methods for shear-thinning hemostats, including thermoresponsive hemostats

Abstract

The present disclosure generally relates to methods and systems for shear-thinning hemostats, for example, to use on a site of hemorrhage. In some embodiments, the hemostat is a solution comprising a polymer and a plurality of nanoparticles, where the solution is thixotropic, shear-thinning, and/or comprises a lower critical solution temperature. In some embodiments, the injectable hemostat is a liquid at 25° C. and a solid at 37° C. In some embodiments, the disclosure relates to injecting a solution into a site of hemorrhage in a subject, where upon injecting the solution, a plug is formed, thus limiting blood loss in the subject. In some embodiments, injecting the solution within the site of hemorrhage reduces the time for the plug to form, relative to sites not treated with the liquid solution.

What is claimed is: 
     
         1 . An article, comprising:
 a thermoresponsive polymer dissolved in solution; and   a plurality of nanoparticles suspended in the solution;   wherein the solution is thixotropic and comprises a lower critical solution temperature (LCST) of at least 25° C.   
     
     
         2 . The article of  claim 1 , wherein the thermoresponsive polymer comprises a poly(acrylamide). 
     
     
         3 . The article of  claim 2 , wherein the poly(acrylamide) comprises poly(N-isopropyl acrylamide). 
     
     
         4 . The article of  claim 2 or 3 , wherein the poly(acrylamide) comprises poly(N,N-diethyl acrylamide). 
     
     
         5 . The article of any one of  claims 2-4 , wherein the poly(acrylamide) comprises poly(N-ethylmethacrylamide). 
     
     
         6 . The article of any one of  claims 1-5 , wherein the thermoresponsive polymer comprises a poly(caprolactam). 
     
     
         7 . The article of  claim 6 , wherein the poly(caprolactam) comprises poly(N-vinyl caprolactam). 
     
     
         8 . The article of any one of  claims 1-7 , wherein the thermoresponsive polymer comprises a poly(vinyl ether). 
     
     
         9 . The article of  claim 8 , wherein the poly(vinyl ether) comprises a poly(methyl vinyl ether). 
     
     
         10 . The article of any one of  claim 8 or 9 , wherein the poly(vinyl ether) comprises a poly(2-ethoxyethyl vinyl ether). 
     
     
         11 . The article of any one of  claims 1-10 , wherein the thermoresponsive polymer is a homopolymer. 
     
     
         12 . The article of any one of  claims 1-11 , wherein the thermoresponsive polymer is a block copolymer. 
     
     
         13 . The article of any one of  claims 1-12 , wherein the thermoresponsive polymer is a branched polymer. 
     
     
         14 . The article of any one of  claims 1-13 , wherein the thermoresponsive polymer is dissolved in the solution at a concentration of between 0.25 g/dL to 5 g/dL. 
     
     
         15 . The article of any one of  claims 1-14 , wherein the plurality of nanoparticle comprises a synthetic smectic clay. 
     
     
         16 . The article of any one of  claims 1-15 , wherein the plurality of nanoparticles comprises a ceramic nanoparticle. 
     
     
         17 . The article of any one of  claims 1-16 , wherein the plurality of nanoparticles comprises a metal nanoparticle. 
     
     
         18 . The article of any one of  claims 1-17 , wherein the plurality of nanoparticles comprises a polymeric nanoparticle. 
     
     
         19 . The article of any one of  claims 1-18 , wherein the plurality of nanoparticles comprises a lipid nanoparticle. 
     
     
         20 . The article of any one of  claims 1-19 , wherein the plurality of nanoparticles comprises a carbon-based nanoparticle. 
     
     
         21 . The article of any one of  claims 1-20 , wherein the plurality of nanoparticles comprises Laponite. 
     
     
         22 . The article of any one of  claims 1-21 , wherein the plurality of nanoparticles comprises a negatively charged outer surface. 
     
     
         23 . The article of any one of  claims 1-22 , wherein the plurality of nanoparticles comprises a positively charged outer surface. 
     
     
         24 . The article of any one of  claims 1-23 , wherein the plurality of nanoparticles comprises a coating. 
     
     
         25 . The article of any one of  claims 1-24 , wherein the plurality of nanoparticles is present in the solution at a concentration of between 0.05 g/dL and 5 g/dL. 
     
     
         26 . The article of any one of  claims 1-25 , wherein the plurality of nanoparticles degrade into nontoxic components. 
     
     
         27 . The article of any one of  claims 1-26 , wherein the solution is thixotropic at a shear rate of between 0.1 1/s and 1.0 1/s. 
     
     
         28 . The article of any one of  claims 1-27 , wherein the solution comprises a hydrogel between 32° C. and 37° C. 
     
     
         29 . The article of  claim 28 , wherein the hydrogel has a storage modulus of between 10 and 1000 Pa. 
     
     
         30 . The article of any one of  claims 1-29 , wherein the solution has a viscosity of between 1 and 100 Pa see at 25° C. 
     
     
         31 . The article of any one of  claims 1-30 , wherein the solution has a viscosity of between 1 and 1000 Pa see at 37° C. 
     
     
         32 . The article of any one of  claims 1-31 , wherein the solution requires an injection force of between 1 and 10 N. 
     
     
         33 . The article of any one of  claims 1-32 , wherein the solution further comprises one or more antibiotics. 
     
     
         34 . The article of any one of  claims 1-33 , wherein the solution further comprises one or more clotting factors. 
     
     
         35 . The article of  claim 34 , wherein the one or more clotting factors comprises thrombin. 
     
     
         36 . The article of any one of  claim 34 or 35 , wherein the one or more clotting factors comprises clotting factor XIII. 
     
     
         37 . The article of any one of  claims 34-36 , wherein the one or more clotting factors comprises clotting factor VII. 
     
     
         38 . The article of any one of  claims 1-37 , wherein the solution further comprises one or more antifibrinolytic agents. 
     
     
         39 . The article of  claim 38 , wherein the one or more antifibrinolytic agents comprises tranexamic acid. 
     
     
         40 . The article of any one of  claim 38 or 39 , wherein the one or more antifibrinolytic agents comprises epsilon-aminocaproic acid. 
     
     
         41 . The article of any one of  claims 1-40 , wherein the article is a hemostatic agent. 
     
     
         42 . An article, comprising:
 a thermoresponsive polymer dissolved in a thixotropic solution, wherein the polymer is insoluble in the solution at between 32° C. and 37° C.; and   a plurality of charged particles suspended in the thixotropic solution.   
     
     
         43 . A method, comprising:
 injecting a liquid solution into a site of hemorrhage in a subject, wherein the liquid solution comprises a polymer and a plurality of nanoparticles, wherein upon injecting the liquid solution the polymer produces a hydrogel and the plurality of nanoparticles concentrate one or more clotting factors at the site of hemorrhage; and   forming a plug within the site of hemorrhage.   
     
     
         44 . The method of  claim 43 , wherein the plug comprises the hydrogel. 
     
     
         45 . The method of any one of  claim 43 or 44 , wherein forming the hydrogel uses the subject's body temperature. 
     
     
         46 . The method of  claim 45 , wherein using the subjects body temperature causes the polymer to undergo a phase change from a liquid to a solid. 
     
     
         47 . The method of any one of  claims 43-46 , wherein forming the hydrogel uses an external heat source. 
     
     
         48 . The method of  claim 47 , wherein using the external heat source causes the polymer to undergo a phase change from a liquid to a solid. 
     
     
         49 . The method of any one of  claims 43-48 , wherein the plug comprises at least a part of the plurality of nanoparticles. 
     
     
         50 . The method of any one of  claims 43-49 , wherein the plurality of nanoparticles comprises a negatively charged outer surface. 
     
     
         51 . The method of any one of  claims 43-50 , wherein the plurality of nanoparticles comprises a positively charged outer surface. 
     
     
         52 . The method of any one of  claims 43-51 , wherein the plurality of nanoparticles comprises Laponite. 
     
     
         53 . The method of any one of  claims 43-52 , wherein the plurality of nanoparticles binds to one or more clotting factors. 
     
     
         54 . The method of any one of  claims 43-53 , wherein the plug comprises a blood clot. 
     
     
         55 . The method of  claim 54 , wherein the blood clot has a maximum amplitude of between 55 mm to 80 mm. 
     
     
         56 . The method of any one of  claim 54 or 55 , wherein the blood clot has a K value of between 1 min and 4 mins. 
     
     
         57 . The method of any one of  claims 54-56 , wherein the blood clot has an R-value of between 4 min and 8 min. 
     
     
         58 . The method of any one of  claims 54-57 , wherein the blood clot has an alpha-angle of between 47 degrees and 74 degrees. 
     
     
         59 . The method of any one of  claims 54-58 , wherein the blood clot has an LY30% value of between 0% and 8% of the total mass of the blood clot. 
     
     
         60 . The method of any one of  claims 43-59 , wherein the polymer is insoluble in the liquid solution at a temperature of between 32° C. and 37° C. 
     
     
         61 . The method of any one of  claims 43-60 , wherein the polymer comprises a poly(acrylamide). 
     
     
         62 . The method of any one of  claims 43-61 , wherein the polymer comprises a poly(caprolactam). 
     
     
         63 . The method of any one of  claims 43-62 , wherein the polymer comprises a poly(vinyl ether). 
     
     
         64 . A method, comprising:
 administering, to a site of hemorrhage in a subject, a solution comprising a polymer and charged silicate nanoparticles, wherein upon administration, the solution is heated by blood at the site of hemorrhage to produce a hydrogel comprising the polymer and clotting proteins inter-dispersed with the charged silicate nanoparticles.   
     
     
         65 . The method of  claim 64 , wherein the hydrogel has a maximum amplitude of between 55 mm to 80 mm. 
     
     
         66 . The method of any one of  claim 64 or 65 , wherein the hydrogel has a K value of between 1 min and 4 mins. 
     
     
         67 . The method of any one of  claims 64-66 , wherein the hydrogel has an R-value of between 4 min and 8 min. 
     
     
         68 . The method of any one of  claims 64-67 , wherein the hydrogel has an alpha-angle of between 47 degrees and 74 degrees. 
     
     
         69 . The method of anyone of  claims 64-68 , wherein the hydrogel has an LY30% value of between 0% and 8% of the total mass of the blood clot. 
     
     
         70 . A thixotropic solution, comprising:
 a polymer able to form a hydrogel at a temperature between 32° C. and 37° C.; and   charged lithium sodium magnesium silicate particles suspended in the thixotropic solution.   
     
     
         71 . An article, comprising:
 a solution comprising a polymer able to form a hydrogel at a temperature between 32° C. and 37° C., and charged lithium sodium magnesium silicate particles.   
     
     
         72 . The article of  claim 71 , wherein the polymer comprises a poly(acrylamide). 
     
     
         73 . The article of  claim 72 , wherein the poly(acrylamide) polymer is not a poly(N-isopropylacrylamide) polymer. 
     
     
         74 . The article of any one of  claim 72 or 73 , wherein the poly(acrylamide) polymer comprises a poly poly(N,N-diethyl acrylamide) polymer. 
     
     
         75 . The article of any one of  claims 72-74 , wherein the poly(acrylamide) polymer comprises a poly(N-ethylmethacrylamide) polymer. 
     
     
         76 . The article of any one of  claims 71-75 , wherein the polymer comprises a poly(caprolactam). 
     
     
         77 . The article of  claim 76 , wherein the poly(caprolactam) comprises poly(N-vinyl caprolactam). 
     
     
         78 . The article of any one of  claims 71-77 , wherein the polymer comprises a poly(vinyl ether). 
     
     
         79 . The article of  claim 78 , wherein the poly(vinyl ether) comprises a poly(methyl vinyl ether). 
     
     
         80 . The article of any one of  claim 78 or 79 , wherein the poly(vinyl ether) comprises a poly(2-ethoxyethyl vinyl ether). 
     
     
         81 . The article of any one of  claims 71-80 , wherein the polymer is a homopolymer. 
     
     
         82 . The article of any one of  claims 71-81 , wherein the polymer is a block copolymer. 
     
     
         83 . The article of any one of  claims 71-82 , wherein the polymer is a branched polymer. 
     
     
         84 . The article of any one of  claims 71-83 , wherein the polymer is dissolved in the solution at a concentration of between 0.25 g/dL to 1 g/dL. 
     
     
         85 . The article of any one of  claims 71-84 , wherein the charged lithium sodium magnesium silicate particle comprises Laponite. 
     
     
         86 . The article of any one of  claims 71-85 , wherein the charged lithium sodium magnesium silicate particle is negatively charged. 
     
     
         87 . The article of any one of  claims 71-86 , wherein the charged lithium sodium magnesium silicate particle is positively charged. 
     
     
         88 . The article of any one of  claims 71-87 , wherein the charged lithium sodium magnesium silicate particle comprises a coating. 
     
     
         89 . The article of any one of  claims 71-88 , wherein the charged lithium sodium magnesium silicate particle is present in the solution at a concentration of between 0.05 g/dL and 1 g/dL. 
     
     
         90 . The article of any one of  claims 71-89 , wherein the charged lithium sodium magnesium silicate particles degrade into nontoxic components. 
     
     
         91 . The article of any one of  claims 71-90 , wherein the solution further comprises one or more antibiotics. 
     
     
         92 . The article of any one of  claims 71-91 , wherein the solution further comprises one or more clotting factors. 
     
     
         93 . The article of  claim 92 , wherein the one or more clotting factors comprises thrombin. 
     
     
         94 . The article of any one of  claim 92 or 93 , wherein the one or more clotting factors comprises clotting factor XIII. 
     
     
         95 . The article of any one of  claims 92-94 , wherein the one or more clotting factors comprises clotting factor VII. 
     
     
         96 . The article of any one of  claims 71-95 , wherein the solution further comprises one or more antifibrinolytic agents. 
     
     
         97 . The article of  claim 96 , wherein the one or more antifibrinolytic agents comprises tranexamic acid. 
     
     
         98 . The article of any one of  claim 96 or 97 , wherein the one or more antifibrinolytic agents comprises epsilon-aminocaproic acid. 
     
     
         99 . The article of any one of  claims 71-98 , wherein the article is a hemostatic agent. 
     
     
         100 . An article, comprising:
 a solution comprising poly(N-vinyl caprolactam) and charged lithium sodium magnesium silicate particles.   
     
     
         101 . A method, comprising:
 administering, to a site of hemorrhage in a subject, a solution comprising a polymer and charged silicate nanoparticles; and   heating the solution at the site of hemorrhage to the subject's temperature to produce a hydrogel comprising the polymer and clotting proteins inter-dispersed with the charged silicate nanoparticles.   
     
     
         102 . The method of  claim 101 , wherein the charged silicate nanoparticle binds one or more clotting proteins. 
     
     
         103 . The method of  claim 102 , wherein binding one or more clotting proteins to the charged silicate nanoparticles concentrates the clotting factors within the site of hemorrhage. 
     
     
         104 . The method of  claim 101-103 , wherein the hydrogel further comprises a blood clot. 
     
     
         105 . The method of  claim 104 , wherein the blood clot has a maximum amplitude of between 55 mm to 80 mm. 
     
     
         106 . The method of any one of  claim 104 or 105 , wherein the blood clot has an K value of between 1 min and 4 mins. 
     
     
         107 . The method of any one of  claims 104-106 , wherein the blood clot has an R-value of between 4 min and 8 min. 
     
     
         108 . The method of any one of  claims 104-107 , wherein the blood clot has an alpha-angle of between 47 degrees and 74 degrees. 
     
     
         109 . The method of any one of  claims 104-108 , wherein the blood clot has an LY30% value of between 0% and 8% of the total mass of the blood clot. 
     
     
         110 . The method of any one of  claims 101-109 , wherein heating the solution to produce the hydrogel uses the subjects body temperature. 
     
     
         111 . The method of any one of  claims 101-110 , wherein heating the solution to produce the hydrogel uses an external heat source. 
     
     
         112 . The method of any one of  claims 101-111 , wherein heating the solution causes the polymer to undergo a phase change from a liquid to a solid.